tbuckley/cabot-search huggingface dataset:
P1201: A REAL-WORLD STUDY OF CHIDAMIDE FOR PATIENTS WITH PERIPHERAL T-CELL LYMPHOMA IN CHINA
Authors: Xin Wang, Ailin Zhao, Shanshan Du, Simeng Gu, Jingqiu Zhou, Ting Niu
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Peripheral T-cell lymphoma (PTCL) is featured with a poor survival outcome. Targeting histone deacetylases (HDACs) has become a novel treatment option for PTCL. Chidamide is the first oral selective HDAC inhibitor. Aims: This observational study aimed to investigate the efficacy and safety of chidamide in patients with PTCL. Methods: From June 2015 to April 2022, 48 PTCL patients treated with chidamide were included in this study. Objective responses, progression-free survival (PFS), overall survival (OS), and safety were analyzed. Results: The median age was 59 years (range, 30 years to 85 years). Angioimmunoblastic T-cell lymphoma (AITL, 57.1%) was the main pathological subtype, followed by PTCL-not otherwise specified (PTCL-NOS, 14.3%), NK/T-cell lymphoma (NKTCL, 8.2%), anaplastic large cell lymphoma (ALCL, 6.1%) and other subtypes (14.3%). 77.6% of patients were previously untreated (38/49). 91.8% of patients had stage Ⅲ/Ⅳ disease (45/49). Thirty-three patients achieved objective responses with an overall response rate (ORR) of 67.4%, including 21 patients with complete response (CR). The 2-year PFS rate and 2-year OS rate were 51.5% and 68.5%, respectively. Among the 27 previously untreated patients who received chidamide combined with chemotherapy, the ORR of all various PTCL subtypes, AITL and PTCL-NOS were 85.2%, 68.8% and 75.0%, respectively. The most common adverse events (AEs) were hematological toxicities. 24.5% of patients reduced the dosage or stoped using chidamide due to AEs (12/49). No treatment-related death occurred. Summary/Conclusion: The favorable efficacy and safety profiles indicate that chidamide would be a new therapeutic option in patients with PTCL. Keywords: Safety, Peripheral T-cell lymphoma, Inhibitor, Clinical outcome
Author Correction: A shared neural basis underlying psychiatric comorbidity
Authors: Chao Xie, Shitong Xiang, Chun Shen, Xuerui Peng, Jujiao Kang, Yuzhu Li, Wei Cheng, Shiqi He, Marina Bobou, M John Broulidakis, Betteke Maria van Noort, Zuo Zhang, Lauren Robinson, Nilakshi Vaidya, Jeanne Winterer, Yuning Zhang, Sinead King, Tobias Banaschewski, Gareth J Barker, Arun L W Bokde, Uli Bromberg, Christian Büchel, Herta Flor, Antoine Grigis, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Hervé Lemaître, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Juliane H Fröhner, Ulrike Schmidt, Julia Sinclair, Michael N Smolka, Argyris Stringaris, Henrik Walter, Robert Whelan, Sylvane Desrivières, Barbara J Sahakian, Trevor W Robbins, Gunter Schumann, Tianye Jia, Jianfeng Feng
Journal: Nature Medicine (2023)
P1110: REAL-WORLD TREATMENT PATTERNS OF BRUTON TYROSINE KINASE INHIBITORS (BTKI) IN PATIENTS WITH MANTLE CELL LYMPHOMA (MCL) IN COMMUNITY ONCOLOGY PRACTICES IN THE UNITED STATES (US)
Authors: Bijal Shah, Mei Xue, Keri Yang, Sizhu (Tom) Liu, Boxiong Tang
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: Real-world data on BTKi use in MCL remain limited. This study aimed to examine US real-world BTKi treatment pattern, duration, and adherence in MCL patients. Aims: This study aimed to examine US real-world BTKi treatment pattern, duration, and adherence in MCL patients. Methods: This retrospective observational study used electronic medical records (EMR) data from Integra Connect database in 18 US community-based oncology practices. Adults with MCL diagnosis on ≥2 separate dates who started BTKi therapy between 1/1/2019 and 11/30/2021 were included. EMR data was collected to ensure adequate medical history and ≥6-months follow up period. Index date was defined based on the use of one of the 3 BTKi: zanubrutinib, acalabrutinib, and ibrutinib for 3 BTKi patient cohorts. Sociodemographic and clinical characteristics, comorbidities, and treatment patterns were examined by each BTKi group. Baseline comorbidities were collected ≤90 days prior to index date based on diagnosis records. Treatment duration was calculated based on EMR and claims until end of follow up. Discontinuation data was based on unstructured physician notes. Kaplan-Meier analysis was used to compare treatment duration between the 3 BTKi groups. Results: In 402 MCL patients identified to start BTKi therapy (44 zanubrutinib; 161 acalabrutinib; 197 ibrutinib), the median age (range) at BTKi therapy start was 75 (56-89) years in zanubrutinib, 76 (36-89) in acalabrutinib, and 72 (36-89) in ibrutinib group (P<0.01; Table). There is no significant difference between the 3 BTKi groups in other baseline characteristics. Half of zanubrutinib patients used other BTKi in prior therapy, with 31.8% switched from other BTKis to zanubrutinib ≤60 days of treatment start. In acalabrutinib group, 29% had prior BTKi use. Given a later approval date, zanubrutinib group had a relative shorter mean follow-up period (493 days [d]) vs acalabrutinib (701 d) and ibrutinib (746 d). Nevertheless, zanubrutinib patients had significantly longer median treatment duration (292 d) vs acalabrutinib (259 d) and ibrutinib (149 d) (P<0.01). Summary/Conclusion: Real-world EMR data from US community-based oncology practices suggested significantly longer treatment duration and adherence in MCL patients treated with zanubrutinib compared with acalabrutinib or ibrutinib. Further analyses on long term utilization are needed upon data maturation.Keywords: Real world data, Non-Hodgkin’s lymphoma, Mantle cell lymphoma
P427: CEBP/Α CONTROLS A CORE DIFFERENTIATION PROGRAM PERTURBED IN HOX-INDUCED LEUKEMIA
Authors: Maria-Paz Garcia-Cuellar, Selin Akan, Robert Slany
Journal: HemaSphere (2023)

Background: An arrest of hematopoietic differentiation is a major prerequisite for the development of acute leukemia. Up to date, most research has been conducted to elucidate the molecular function of oncogenic alterations. In contrast, genetic control of normal blood cell differentiation is less known. Aims: Here we study the control circuits downstream of Cebp/α, a transcription factor that regulates hematopoietic differentiation. Cebp/α acts as tumor-suppressor and the Cebp/α gene is frequently inactivated by mutations in acute myeloid leukemia. In addition, we determine how Hoxa9, a paradigmatic oncogene in AML, perturbs maturation and if this can be bypassed to revert the transformation process. Methods: Based on advanced degron-techniques we developed a system that allows select expression of the two known Cebp/α isoforms p30 and p42 in primary HSPCs derived from murine bone marrow. Because only p42 prompts differentiation, while p30 supports proliferation, a comparison of isoform specific genomics and transcriptomics data was able to identify p42 specific events. Results: Despite congruent genomic distribution of p30 and p42 proteins as detected by ChIP, both proteins guided largely non-identical expression programs. Most importantly, we identified three p42-specific targets that are major drivers of hematopoeitic maturation. Egr1, Serpinb2, and Trib1 are under exclusive control of p42 with the transcription factor Egr1 acting as master differentiation inducer controlling key aspects of development like nuclear segmentation, shutdown of precursor expression programs and, importantly, cell cycle exit through induction of CDK inhibitors. Serpinb2 ensures that differentiation becomes unidirectional by stabilizing the Egr1 response. Finally, Trib1 feeds into a negative feedback loop by inducing various phosphorylation events. While counter-intuitive at first glance, this is necessary to establish a “latent” differentiation program that can be precisely triggered by signaling, a feature that obviously cannot be attained by trancriptional control alone. HoxA9 impacts at the final endpoint of the differentiation pathway through its major downstream mediator Myc without affecting Cebp/α isoform ratios. Finally, we show that oncogenic activity can be bypassed and normal differentiation is restored by altering the cytokine environment. Summary/Conclusion: Our data shed new light on the mechanism of cellular differentiation. Moreover, we provide a plausible explanation for the frequent dual occurrence of signaling and transcriptional mutations in AML and we uncover new possible routes for differentiation therapies. Keywords: AML, CEBPa, Differentiation
P1143: ZANUBRUTINIB PLUS CYTARABINE IN PATIENTS WITH REFRACTORY/RELAPSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Zhiguang Lin, Jingjing MA, Yan MA, Qing LI, Hui Kang, Mengxue Zhang, Bobin Chen
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Primary central nervous system lymphoma (PCNSL) is a rare subtype of aggressive extranodal non-Hodgkin lymphoma. Currently, there is no consensus on the treatment of refractory or relapsed PCNSL (r/r PCNSL). Bruton tyrosine kinase (BTK) inhibitors have shown some activity in PCNSL. Zanubrutinib is a new generation of highly selective and irreversible BTK inhibitor that has shown efficacy in a variety of B cell lymphomas. Aims: This study aims to evaluate the efficacy and safety of zanubrutinib combined with cytarabine as a new treatment for r/r PCNSL. Methods: This was a single-center, single-arm, phase 2 trial. The study used Simon’s two-stage design and planned to enroll 12 patients in stage 1. The remaining 22 patients would be recruited in stage 2 if more than 4 responses were observed in stage 1. Patients would receive high-dose cytarabine (3.0 g/m2) for 2 days and zanubrutinib (160 mg twice daily) for 21 days each cycle for up to 6 cycles. The primary endpoint was overall response rate (ORR), defined as the proportion of patients whose best response was complete remission (CR), unconfirmed complete remission (CRu), or partial remission (PR). The secondary endpoint was progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety profile. Results: A total of 34 patients were enrolled and analyzed. The median age was 62 years (range, 26 to 75 years). The median follow-up was 19 months. The overall response rate was 64.7% (95% confidence interval (CI), 47.9% to 78.5%) with a complete remission or unconfirmed complete remission rate of 47.1% (16/34) and a partial remission rate of 17.6% (6/34). The median PFS was 4.5 months (95% CI, 1.5 to 9.4) and the median OS was 18 months (95%CI, 9.5 to not estimable). The median DOR was 9 months (95%CI, 3.2 to not estimable). The most common type of treatment-emergent adverse events (TEAEs) was hematological TEAEs, including thrombocytopenia (55.9%), anemia (47.1%), and neutropenia (23.5%). A total of 16 (47.1%) patients experienced grade 3/4 thrombocytopenia. Common nonhematologic TEAEs were pneumonitis (14.7%), skin infection (8.8%), and increased blood bilirubin (14.7%). No treatment-related death occurred. Summary/Conclusion: Zanubrutinib combined with high-dose cytarabine showed promising efficacy in r/r PCNSL with an acceptable safety profile. The trial is registered at www.chictr.org.cn as #ChiCTR2000039229.Keywords: Cytarabine, CNS lymphoma, Bruton’s tyrosine kinase inhibitor (BTKi), Clinical trial
PB2697: LONG TERM PEJORATIVE IMPACT OF LENALIDOMIDE MAINTENANCE ON HEALTH-RELATED QUALITY OF LIFE IN CHRONIC LYMPHOCYTIC LEUKEMIA. ANCILLARY STUDY OF THE PHASE III CLL6-RESIDUUM TRIAL
Authors: Stephane Wasse, Tienhan Sandrine Dabakuyo-Yonli, Dan Engeler, David Gottlieb, Therese Aurran Schleinitz, Florence Cymbalista, Marc Maynadie
Journal: HemaSphere (2023)

Topic: 35. Quality of life and palliative care Background: The CLL6 RESIDUUM trial was a joint study of the Australian Leukaemia and Lymphoma Group (ALLG) and the French Innovative Leukemia Organization (FILO) that analyzes the role of 2 years lenalidomide consolidation therapy in patients undergoing front-line treatment for CLL who do not enter MRD negative complete remission. Aims: An ancillary study of this trial aimed to assess the health-related quality of life (HRQoL) of patients with chronic lymphocytic leukemia (CLL) receiving a two year maintenance of lenalidomide (LEN) or observation (OBS) after classical immunochemotherapy leaving them with detectable minimal residual disease (MRD). Methods: Data from French patients involved in this part of the trial were used. Patients were asked to complete the EORTC QLQ-C30 version 3 questionnaire at baseline and at the end of maintenance months 3, 6, 12, 18 and 24 post randomization. Repeated measures mixed-effects models were used to assess the mean Health Related Quality of Life (HRQoL) changes from baseline to each checkpoint and for each HRQoL scale. Results: Half of the patients in each arm were over 70-year-old. Baseline data showed overall a good global health status with mean scores of 76.3 and 72.1 in the LEN and OBS arms respectively, on the 0-100 scale. At 12 months, LEN patients had significantly more diarrhea than OBS patients (p=0.003) and social functioning was significantly impaired at month 18 (p=0.05). The clinical significance of a 10-point difference appeared in the LEN arm for dyspnea and digestive disorders from month 12 on. Multivariate analysis showed a deleterious effect of LEN on global health (p=0.02) and functional scales (p=0.003). Summary/Conclusion: Supplementation with lenalidomide as maintenance therapy in CLL leads to long-term health deterioration, compared to off-therapy patients. This study provides reference HRQoL values for comparison in the developing new therapeutic approaches of CLL management. Keywords: Clinical trial, Chronic lymphocytic leukemia, Patient reported outcomes, Quality of life
PB2497: HEMATOLOGIC TOXICITIES WITH IMMUNOTHERAPY IN CANCER PATIENTS AT THE ALLAN BLAIR CANCER CENTRE: RETROSPECTIVE DATA COLLECTION STUDY
Authors: Amani Khan, Ibraheem Othman, Shubrandu Sanjoy, Sandy Kassir, Osama Souied
Journal: HemaSphere (2023)

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Immunotherapy, particularly checkpoint inhibitors, has demonstrated significant clinical benefits in the treatment of various malignancies. However, these novel therapies can also lead to serious and potentially life-threatening toxicities. This necessitates further investigation into the incidence and nature of these toxicities in clinical practice. Aims: The aim of this retrospective chart review study was to identify the proportion and context of patients treated at the Allan Blair Cancer Centre who experienced immunotherapy-related toxicities. We focused specifically on hematologic toxicities in order to provide clinicians with a better understanding of the risks associated with this drug class. Methods: We reviewed a total of 486 patient charts from the Saskatchewan Cancer Agency, pertaining to patients who received immunotherapy for any indication between 2013, when immunotherapy began being administered within the system, and May 30th, 2020. Patients with various tumour types who received anti-programmed cell death 1 (PD-1) and/or anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), with or without chemotherapy, and experienced anemia, neutropenia, or thrombocytopenia within a time frame of therapy were included. Breast, gastrointestinal, sarcoma, and neuroendocrine tumours were excluded. We collected data on the incidence of hematologic toxicities and the management of these toxicities in clinical practice, using a data collection tool in REDCap. Results: Among the charts identified, 430 patients met the inclusion criteria. The mean age was 70.3±11.2 years, and 50.8% were female. The overall rate of immunotherapy-related reactions was 47.3%, whereas anemia, thrombocytopenia and neutropenia were 93.5%, 21.3% and 11.3%, respectively. Patients with combination immunotherapy and chemotherapy had a lower incidence of anemia (4.1% versus 15.3%, P<0.001), thrombocytopenia (6.9% versus 28.6%, P<0.001) and neutropenia (5.9% versus 65.4%, P<0.001). Summary/Conclusion: The incidence of immunotherapy-related anemia was the most significant finding in our data. Most of the reactions were less common in the combination therapy cohort. The outcome of this research may assist clinicians in identifying the risks burdening patients undergoing cancer treatment and establishing best management practices to reduce patient morbidity and mortality. Keywords: Toxicity, Cancer immunotherapy
P908: IDENTIFICATION OF CYTOKINES ASSOCIATED WITH RESPONSE AND CYTOKINE RELEASE SYNDROME – ANALYSIS OF MAGNETISMM-3 COHORT A
Authors: Katja Weisel, Nizar J Bahlis, Paula Rodríguez-Otero, Andrea Viqueira, Shen-Wu Wang, Sangeetha Sathiah, Douglas Robinson, Thomas O’brien, Hang Quach
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: MagnetisMM-3 (NCT04649359) is a phase 2 study of elranatamab monotherapy in patients with multiple myeloma refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Promising efficacy and safety have been observed in patients who were naïve to B-cell maturation antigen (BCMA)-directed therapy (Cohort A) in MagnetisMM-3 (Bahlis et al., ASH 2022). Aims: This analysis examined the relationship between cytokine levels and elranatamab response, and cytokine levels and cytokine release syndrome (CRS), in BCMA-naïve patients from MagnetisMM-3. Methods: In MagnetisMM-3, patients received subcutaneous elranatamab in 28-day cycles with step-up doses of 12 mg on C1D1 and 32 mg on C1D4 followed by 76 mg QW beginning C1D8. Serum samples were collected on C1D1 prior to first priming dose, and on C1D2, pre-dose C1D4, C1D5, pre-dose C1D8, C1D15, and C1D22. Levels of 45 peripheral cytokines were analyzed by proximity extension assay and a longitudinal mixed effects model was applied to each cytokine separately. Cytokines with a significant 2-fold differential expression in responders (defined as patients with best overall response of very good partial response [VGPR] or better) vs non-responders (defined as patients with best overall response of partial response or worse) and in patients with CRS vs no CRS at any timepoint are reported. Clinical data cutoff was Oct 2022 with a median follow up of 10.4 months. Results: Baseline levels of IL-6 (2.6-fold), IL-17C (2.0-fold), and MIP-1α (2.1-fold) were lower in patients who achieved a response. After the first priming dose, 13 cytokines in the panel, including CCL8, IFN-γ, IL-2, and IL-27, were differentially expressed in responders vs non-responders. At baseline, no cytokines were found to predict CRS. After the first priming dose, 18 cytokines in the panel, including CCL8, IFN-γ, IL-10, IL-2, IL-27, IL-6 (Figure), and IL-17A, were differentially expressed in patients with CRS vs no CRS. The maximal differential expression for 17/18 cytokines occurred at C1D2, ~24 hours post the first priming dose. Summary/Conclusion: Lower baseline levels of IL-6, IL-17C, and MIP-1α correlated with a response of VGPR or better in BCMA-naïve patients from MagnetisMM-3, suggesting that lower levels of these cytokines might reflect a favorable immune environment. Many cytokines were differentially expressed at higher levels in patients who experienced CRS vs those who did not; the most prominent cytokines included CCL-8, IFN-γ, and IL-10. The timing of induction of CCL-8, IFN-γ, and IL-10 occurred by C1D2 suggesting a potential contribution of these cytokines in driving CRS.Keywords: Cytokine, Clinical trial, Multiple myeloma, Myeloma
PB1704: LEDGF/P75 ASSOCIATED WITH CHEMORESISTANCE IN MIXED-LINEAGE LEUKEMIA
Authors: Muluembet Akele, Siska Van Belle, Alessandro Canella, Frauke Christ, Zeger Debyser
Journal: HemaSphere (2023)

Topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research Background: Approximately 10% of leukemia patients worldwide present with KMT2A rearrangements, mostly affecting pediatric patients. Overall, KMT2A rearrangements are linked to a poor prognosis with a low 5-year survival mainly due to tumor relapse and lack of specific treatment. LEDGF/p75, a co-transcriptional activator tethers the KMT2A fusion protein complex to its target genes (e.g. HoxA family, Meis1, Cdk6), driving leukemogenesis. Our lab has shown that LEDGF/p75 is essential for leukemic transformation in mice yet is dispensable for normal hematopoiesis. We recently demonstrated that LEDGF/p75 drives chemoresistance in a KMT2A-r cell line. Aims: Based on our recent finding that LEDGF/p75 mediates chemoresistance in a KMT2A-r cell line (Thp1), we further explored the role of LEDGF/p75 levels in cell survival and chemoresistance in multiple wild-type and KMT2A-r cell lines associated with AML or ALL. Methods: To investigate the role of LEDGF/p75 in chemoresistance in ALL, we stably knocked down LEDGF/p75 using a lentiviral vector that expresses LEDGF/p75 miRNA in an ALL KMT2A-r (SEM) or a wild-type KMT2A cell line (Nalm-6). We investigated the effect of LEDGF/p75 depletion on the sensitivity to the chemotherapeutic agent cytarabine, a DNA intercalating agent used in leukemia treatment. We analyzed drug sensitivity using the WST-1 cell proliferation assay. We assessed the level of apoptosis by flow cytometry using annexin V and propidium iodide staining. Additionally, we analyzed the level of activated caspase3 using western blotting. Results: As shown before LEDGF/p75 depletion in Thp1 cells, an AML cell line with KMT2A-r, leads to increased sensitivity (IC50 = 0.22 ± µM) to cytarabine compared to control Thp1 cells (IC50 = 2.86 ± µM). Similarly, the MOLM-13 (AML, KMT2A-r) cell line which naturally expresses very low levels of LEDGF/p75 also showed high sensitivity to cytarabine (IC50 = 0.11 ± µM). Overexpression of LEDGF/p75 in those cells resulted in increased proliferation and reduced apoptosis. On the contrary, LEDGF/p75-depletion in SEM cells (SEM LEDGF/p75 KD), an ALL cell line with KMT2A-r, resulted in increased proliferation and lower apoptosis upon cytarabine treatment compared to cells expressing mock miRNA. Cytarabine treated SEM LEDGF/p75 KD cells displayed a lower level of caspase3 and annexin/PI-positive cells. The same trend was observed in Nalm-6, an ALL cell line with wild-type KMT2A. Summary/Conclusion: Our data suggest that the LEDGF/p75 expression level plays a critical role in chemoresistance in leukemic cell lines with opposite effects in AML and ALL. Understanding the exact mechanism of LEDGF/p75-mediated chemoresistance in AML could provide relevant insights into the development of novel strategies to treat leukemia by targeting LEDGF/p75. Keywords: 11q23, Drug resistance, Cytarabine, Mixed lineage leukemia